Pain Society of the Carolinas 2015: Nerve Injury and Neuropathy Thomas Buchheit, MD Associate Professor Director of Pain Medicine Department of Anesthesiology Duke University Medical Center Durham VAMC

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Disclosures

•  Consulting: –  Bioventus –  DARA Bioscience –  Thar Pharmaceuticals

•  Research funding: –  Department of Defense: CDMRP DM102142

Outline

•  Anatomy and imaging •  Physiology of nerve injury •  Current Therapies •  Future directions

Anatomy: Types of Nerve Injury

The Endoneural Environment

•  Regulation occurs within the perineurium –  Relatively impermeable –  Sensitive to intrafascicular injection –  Permeability altered by Schwann cell, macrophage and mast cell

activity

•  Neuropathies can be considered perturbations of endoneurial homeostasis

Mizisin: Homeostatic regulation of endoneurial microenvironment. Acta Neuropathol. 2011. 121:291

Nerve Response to Injury Neurapraxia

Axonotmesis

Neurotmesis Stewart: Focal Peripheral Neuropathies 2nd, Ed.’93, Praven press

Degrees of Injury •  Neurapraxia: Temporary nerve dysfunction

–  Most patients will see recovery within 3 months or less

•  Axonotmesis: –  Wallerian degeneration

•  axonal and myelin degeneration distal to point of injury –  Preserved epineurium and basal lamina

•  Neurotmesis: –  Complete division of a peripheral nerve and connective

tissue structures •  Will not regenerate along original channels •  May form neuroma at transection site

Compression Neuropathies: Peripheral Nerve

EMG Findings in CTS

•  Most common compressive mononeuropathy (1-5% of population)

•  Edema and thickening of vessel walls in the endoneurium •  Myelin thinning and fibrosis seen

–  Motor nerve conductions slow –  Sensory fibers more sensitive to compression than motor fibers

•  Axon loss can be seen in advanced cases

Compression Neuropathies: Proximal Nerve/DRG

Transection Neuromas

Post Amputation Phenotype Adjudication

Phantom Pain Residual Limb Pain

No Significant Pain

Somatic Neuropathic

NeuromaCRPS

Mosaic Neuralgia

S-Lanss Score ≥ 12Somatic pathology or S-Lanss <12

Positive Tinel'sDoes not meet other criteria

Budapest Clinical Criteria

Significant Pain

CRPS Budapest Clinical Criteria: Symptoms in ¾ of the following categories: Sensory (hyperalgesia or allodynia), Vascular (temperature, skin color), Sweating/Edema, and Motor (weakness, tremor dystonia)/Trophic (hair, skin).

Physical exam signs in 2/4 of the following categories: Sensory (allodynia), Vascular, Sweating/Edema, or Motor/Trophic.

Pain in missing limb Pain in residual limb

PhantomNo Pain RLP Somatic RLP CRPSRLP Neuroma RLP Mosaic

S-LANSS score:

Average Pain ≥ 3

Figure 1. Phenotype Adjudication Algorithm

N=72 N=76

N=31 N=45

N=37N=15

N=8

N=80N=44

Buchheit T, and Van de Ven T,. Pain Phenotypes and Risk Factors Following Traumatic Amputation:. Pain medicine 2015

Pain Phenotype Results

Buchheit T, and Van de Ven T,. Pain Phenotypes and Risk Factors Following Traumatic Amputation:. Pain medicine 2015

Is Phantom Pain a Central of a Peripheral Problem?

Physiology of Nerve Injury

Neuroinflammatory Mechanisms

Ji RR et al. Emerging targets in neuroinflammation-driven chronic pain. Nature. 2014;13:533–548.

Neuroinflammatory Mechanisms

Von Hehn, Baron and Woolf: Deconstructing the neuropathic pain phenotype. Nature 2012

Van Boxem K, Huntoon M, Van Zundert et al. Pulsed Radiofrequency. RAPM 2014;39:149–159.

Neuroinflammatory Mechanisms in Disc Herniation

•  TNF and other cytokines are released by Schwann cells at site of injury and DRG

•  After peripheral nerve injury:

–  25% of ectopic activity at peripheral axon

–  75% at DRG

Inflammation-Driven Phenotypic Change

•  Macrophage infiltration and cytokine release at site of axonal injury and DRG

•  Microglial activation –  Microglia number increase by 2-4 fold in dorsal horn

•  Astrocyte activation persists for months

Ramer et al: Wallerian degeneration neuropathic pain and sympathetic sprouting in DRG. Pain. 1997; 72: 71-78 Raghavendra V et al Anti-hyperalgesic and morphine-sparing actions of propentofylline following nerve injury. Pain 2003:104:655-64 Gao Y-J, Ji R-R. Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther 2010:126;56-68

Neuroma Ectopic Activity

•  Injury leads to: –  Mechanical sensitivity

•  Focal demyelination of A-fibers at site of injury

–  Ectopic activity •  Proliferation of Nav 1.7 and

1.8 channels at injury and DRG

–  Catecholamine sensitivity •  Sympathetic sprouting at

DRG

Scholz and Woolf: Can we conquer pain. Nature Neuroscience. Nov 2002 Blumberg. Discharge afferent fibers from neuroma. Pain. 1984. P 335-53. Amir. Ectopic spike in neurons. J Neurosci. 2005 25(10) 2576-85.

Neuroinflammatory Mechanisms in the Clinic

Common Immune-Associated Neuropathic Pain Syndromes

•  Myelinopathies: –  Autoimmune Neuropathies (Guillain-Barré) –  Chronic inflammatory demyelinating

polyneuropathy (CIDP) •  Multiple sclerosis •  CRPS

CRPS: Inflammatory Mechanism

•  Serum concentrations of IL-6, and TNF-alpha are elevated •  Joint fluid demonstrates increased protein and neutrophils •  Cytokine inhibitors improve symptoms, especially in early warm

CRPS •  Animal model of fracture/casting

–  Demonstrates inflammatory changes that do not occur in soft tissue injury

•  Improved CRPS symptoms in patients treated with IVIG, DMARDs, and bisphosphonates

Wasner et al: CRPS– diagnostic, mechanisms, CNS involvement, and therapy. Spinal Cord 2003 (41) 61-75. Li W-W, and Clark JD. Autoimmunity contributes to sensitization in complex regional pain syndrome. Pain 2014;155:2377–2389.

Neuroinflammation in non-CRPS Neuropathy

•  Small fiber neuropathy: –  Skin biopsy demonstrates increased gene expression of

IL-1β, TNFα, IL-6, IL-8

Uceyler et al. Elevated proinflammatory cytokine expression in skin in small fiber neuropathy. Neurology. 2010 Jun 1;74(22):1806-13

Are there differences in systemic cytokine levels in patients with persistent pain after amputation?

Current Therapies

Smith and Gomez: Local injection therapy of neuromata.J Bone Joint Surg 52A: 71, 1970 Martinez: Efficacy of minocycline after discectomy. An RCT. Pain 2013: 154: 1197

Neurolytic Therapies

Neurolytic Therapies for Neuroma and Nerve Injury Pain

•  Radiofrequency Lesioning •  Cryoneurolysis •  Chemical Neurolysis

–  2 observational trials demonstrating significant improvement in treatment of amputation neuromas

Kirvela O: Treatment of painful neuromas with neurolytic blockade. Pain. May 1990;41(2):161-165. Gruber et al: Sonographically guided phenol installation of stump neuroma: Amer J. Roentgenology. 190 (5): 1263-9, 2008.

Prevention in an Amputation Injury Model

Preventive Analgesic in Amputation Injury

•  Ketamine:1

–  No significant difference in the incidence of phantom pain at 6 months (47% phantom pain in ketamine and 71% in control group, p=0.28)

•  Gabapentin2: –  No effect when started on POD #1 and continued 30 days at

2,400mg/d •  Memantine3:

–  No effect when 20mg/day memantine compared with placebo

1. Hayes C et al. Perioperative intravenous ketamine infusion for the prevention of persistent post-amputation pain: a randomized, controlled trial. Anaesth IntensiveCare2004;32:330 – 8 2. Nikolajsen L. A randomized study of the effects of gabapentin on postamputationpain.Anesthesiology2006;105:1008 –15 3. Nikolajsen L, Gottrup H, Kristensen AG, Jensen TS. Memantine in the treatment of neuropathic pain after amputation:

a randomized, double-blinded, cross-over study. Anesth Analg 2000;91:960 – 6

Preventive Trials for Post-amputation Pain

•  2010 systematic review –  11 studies of epidural and perineural catheter use

•  Good evidence for efficacy in treating acute postoperative pain

•  No robust evidence that preventive techniques reduce the incidence of chronic pain

Ypsilantis: Pre-emptive analgesia for chronic limb pain after amputation for peripheral vascular disease: A systematic review. Ann Vasc Surg 2010; 24:1139-46

Preventive Trials: Is Duration of Therapy Important?

•  Longer-term perineural catheter use: –  Borghi 2010

•  Average catheter duration 30 days •  84% pain free at 12 months

Borghi et al: Prolonged peripheral neural blockade after amputation. 2010 .Anes Analg 111 (5) 1308-1305.

Risk Factors for Post-amputation Pain

!!!!

!Table!4:!!Clinical!risk!factors!for!development!of!post7amputation!chronic!pain!subtypes.!!!The!odds7ratios!for!development!of!chronic!pain!(all!types),!neuropathic!pain,!phantom!limb!pain,!all!types!of!residual!limb!pain,!somatic!residual!limb!pain,!residual!limb!pain!from!presence!of!neuroma,!complex!regional!pain!syndrome,!mosaic!neuropathic!residual!limb!pain!and!all!neuropathic!residual!limb!pain!are!reported!above!with!p7values!in!brackets.!Factors!associated!with!significant!risk!of!a!specific!pain!subtype!(p7value!<0.050)!are!marked!with!an!asterisk!and!italicized.!The!data!presented!in!the!final!column!include!total!patients!with!neuropathic!pain!regardless!of!case!or!control!status.!

!!

Chronic Pain (cases)

Phantom Pain (cases)

RLP (cases)

RLP-Somatic (cases)

RLP-Neuropathic (cases)

RLP-Neuroma (cases)

RLP- CRPS (cases)

RLP-Mosaic (cases)

Neuropathic Pain (All)

OR (CI) [p]

OR (CI) [p]

OR (CI) [p]

OR (CI) [p]

OR (CI) [p]

OR (CI) [p]

OR (CI) [p]

OR (CI) [p]

OR (CI) [p]

Clinical Factor

PCS [p value]

13.39 (1.73-103.87) [0.0016]*

6.20 (0.34-112.49) [0.1876]

3.05 (0.16-59.29) [0.5676]

0.48 (0.15-1.50) [0.194]

2.71 (0.87-8.45) [0.0735]

2.47 (0.85-7.14) [0.0899]

1.82 (0.53-6.20) [0.3474]

1.08 (0.20-5.85) [1.0000]

3.78 (1.28-11.18) [0.0103]*

PTSD-M [p value]

10.08 (1.28-79.14) [0.0099]*

1.72 (0.20-15.14) [1.0000]

2.31 (0.12-45.15) [1.0000]

0.19 (0.04-0.89) [0.0373]*

6.92 (1.44-33.17) [0.0088]*

6.67 (1.71-26.04) [0.0038]*

7.13 (1.98-25.70) [0.0029]*

0.58 (0.07-5.12) [1.0000]

9.28 (2.01-42.88) [0.0010]*

PHQ-9 [p value]

2.40 (0.94-6.13) [0.055]

9.13 (0.51-164.62) [0.0520]

4.46 (0.23-86.00) [0.3036]

0.38 (0.13-1.09) [0.0624]

3.53 (1.22-10.19) [0.0142]*

3.72 (1.36-10.15) [0.0081]*

4.59 (1.42-14.91) [0.010]*

0.71 (0.13-3.79) [1.0000]

4.46 (1.81-10.99) [0.0006]*

Regional Catheter [p value]

0.63 (0.30-1.33) [0.227]

5.00 (0.58-42.80) [0.142]

1.96 (0.19-19.70) [1.0000]

1.24 (0.50-3.12) [0.6423]

0.91 (0.37-2.25) [0.8397}

1.42 (0.58-3.51) [0.4443]

2.09 (0.67-6.49) [0.2034]

0.20 (0.02-1.71) [0.142]

0.44 (0.21-0.92) [0.0269]*

Incidence of Chronic Pain with Regional Catheter Post-Injury

Future directions

We can’t (and shouldn’t?) prevent inflammation after injury.

Can we facilitate recovery and resolution?

Future Treatments

•  Immune modulation •  IVIG •  Bisphosphonates •  Cytokine inhibitors

–  Positive pilot data for etanercept use for neuromas

–  Epigenetic intervention –  Novel pathway discovery

•  Wnt, NOD

Dahl E, Cohen SP. Perineural injection of etanercept as a treatment for postamputation pain. Clin J Pain. 2008 Feb;24(2):172-5

Why aren’t we treating the inflammatory component of CRPS routinely?

What causes these inflammatory and expression changes after injury?

Epigenetic Modifications

Epigenetic Mechanisms

Buchheit T, Van de Ven T, Shaw A. Epigenetics and the transition from acute to chronic pain. Pain medicine 2012;13:1474–1490.

Can we alter gene expression?

Conclusions

•  Proper diagnosis (better phenotyping) is a precursor to improving therapies

•  Neuroinflammation is a part of most neural injury pain states regardless of injury site

•  Preventive techniques may be effective with longer duration of therapy

•  “Next generation” therapies will likely include immune modulation and epigenetic intervention